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Synlett 2007(19): 2971-2974  
DOI: 10.1055/s-2007-990962
LETTER
© Georg Thieme Verlag Stuttgart · New York

Regio- and Stereoselective One-Pot Synthesis of Unknown Oxazoline-Fused Pyridazines by ‘Michael Addition-Pyridazine Cyclization-Oxazoline Cyclization’ Cascade Reactions of 4-Chloro-1,2-diaza-1,3-butadienes with 3-Dimethylaminopropenoates

Orazio A. Attanasi*a, Gianfranco Favia, Paolino Filipponea, Amalija Golobičb, Francesca R. Perrullia, Branko Stanovnikb, Jurij Sveteb
a Istituto di Chimica Organica, Università degli Studi di Urbino ‘Carlo Bo’, Via I Maggetti 24, 61029 Urbino, Italy
e-Mail: orazio.attanasi@uniurb.it;
b Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
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Publication History

Received 5 September 2007
Publication Date:
08 November 2007 (online)

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Abstract

A one-pot, three-step regio- and stereoselective synthesis of unknown functionalized oxazoline-fused pyridazines is reported. The approach involves base-assisted ‘Michael addition-pyridazine cyclization-oxazoline cyclization’ cascade reactions of 4-chloro-1,2-diaza-1,3-butadienes with 3-dimethylaminopropenoates.

Key words

1,2-diaza-1,3-butadienes - 3-dimethylaminopropenoates - Michael additions - cyclizations - oxazoline-fused pyr­idazines

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General Procedure for the Synthesis of II and 3a-k 4-Chloro-1,2-diaza-1,3-butadiene 1a-g and 3-dimethyl-aminopropenoate 2a-d were synthesized by known procedures and were isolated as an E/Z isomeric mixture5,7e and Z-isomer,8 respectively. To a CHCl3 solution (5 mL) of 4-chloro-1,2-diaza-1,3-butadiene 1a-g (1 mmol) was added 3-dimethylaminopropenoate 2a-d (2 mmol) and DIPEA (1 mmol) and the reaction mixture was refluxed for the appropriate time (see Table [1] ). In order to obtain the intermediate II the reaction between 1a and 2a was heated to reflux for 5 h. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (eluent cyclohexane-EtOAc mixtures).

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Data for Methyl (3a S *,4 R *,7a S* )-5-(Aminocarbonyl)-4-(dimethylamino)-7-methyl-2-phenyl-3a,4,5,7a-tetra-hydropyridazino[4,5- d ][1,3]oxazole-3a-carboxylate (3a)
Colorless crystals from cyclohexane-EtOAc, mp 187-191 °C (dec.). IR (mull): νmax = 3403, 3304, 3252, 3159, 1740, 1703, 1681, 1634, 1591 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 2.11 [s, 9 H, CH3 and N(CH3)2], 3.73 (s, 3 H, OCH3), 5.70 (s, 1 H, CH), 5.72 (s, 1 H, CH), 6.61 (br s, 2 H, CONH2, D2O exch.), 7.49 (t, 2 H, J = 8.0 Hz, Ar), 7.61 (t, 1 H, J = 8.0 Hz, Ar), 7.85 (d, 2 H, J = 8.0 Hz, Ar). 13C NMR (100 MHz, DMSO-d 6): δ = 19.70 (q), 42.42 (q), 52.54 (q), 67.20 (d), 71.00 (d), 77.15 (s), 125.45 (s), 128.26 (d), 128.86 (d), 132.76 (d), 142.72 (s), 156.68 (s), 164.05 (s), 168.93 (s). MS: m/z (%) = 359 [M+] (13), 316 (16), 257 (49), 211 (29), 168 (42), 149 (56), 125 (53), 111 (100). Anal. Calcd for C17H21N5O4: C, 56.82; H, 5.89; N, 19.49. Found: C, 56.97; H, 5.68; N, 19.62.

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Crystallographic data for compound 3a have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 657267. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].

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Data for Methyl (3 R *,4 R *,5 R* )-2-(Aminocarbonyl)-4-(benzoylamino)-5-chloro-3-(dimethylamino)-6-methyl-2,3,4,5-tetrahydro-4-pyridazinecarboxylate (II)
White powder from Et2O, mp 133-134 °C (dec.). IR (mull): νmax = 3465, 3342, 3280, 3205, 1735, 1698, 1658, 1581 cm-1. 1H NMR (400 MHz, CDCl3): δ = 2.21 (s, 3 H, CH3), 2.49 [br s, 6 H, N(CH3)2], 3.73 (s, 3 H, OCH3), 4.94 (br s, 1 H, CONH2, D2O exch.), 5.25 (s, 1 H, CH), 5.34 (s, 1 H, CH), 6.47 (br s, 1 H, CONH2), 7.40-7.52 (m, 2 H, Ar), 7.53-7.60 (m, 1 H, Ar), 7.80-7.88 (m, 3 H, Ar and NH, D2O exch.). 13C NMR (100 MHz, CDCl3): δ = 22.26 (q), 43.96 (q), 49.88 (d), 53.97 (q), 59.88 (s), 69.34 (d), 127.80 (d), 129.22 (d), 132.70 (d), 133.38 (s), 144.61 (s), 157.23 (s), 167.60 (s), 170.58 (s). MS: m/z (%) = 360 [M+ - HCl] (65), 317 (100), 257 (10), 214 (14), 196 (23), 187 (30), 111 (69). Anal. Calcd for C17H22N5O4Cl: C, 51.58; H, 5.60; N, 17.69. Found: C, 51.72; H, 5.81; N, 17.48.